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Solving the Cancer Puzzle One Cell at a Time

In Matthew Breen’s lab at North Carolina State University in Raleigh, you won’t see dogs in cages, not even those that are sick with cancer and will soon die.

Instead you will find microscopes. And under those microscopes, cells, and within those cells, chromosomes, the building blocks of what our dogs are. Specifically, you’ll find canine chromosomes being studied to determine just which ones, in which part of an aberrant gene, cause or result from a certain type of cancer. Not just liver cancer, or bone cancer, but lymphosarcoma and hemangiosarcoma.

Breen, who got his doctorate in 1990 from the University of Liverpool and spent years developing techniques that supported the mapping of the canine genome, is helping dogs recover from cancer – one cell at a time.

“All animals have a particular amount of DNA that comprises their genome,” he says. “During speciation and evolution, genomes are reorganized into what I refer to as nature’s biology filing cabinets.

“The filing cabinet represents the genome. Your entire cabinet is alphabetized or organized in some system. If you want to pull out good restaurants in Boston, you know what drawer it’s in…which chromosome. The hanging files effectively represent the genes within the chromosome. The file inside is the sequence of the genes.

“Sometimes the filing system gets reorganized. In addition to not being able to find what you want, the file is actually in the wrong drawer or in the wrong place in the same drawer.” When that sequence is out of place, “the genes start to interact with each other in a way they wouldn’t have done,” he says.

An Early Inspiration

That’s exactly what happened to Breen’s Border Collie-Terrier mix, Penny, when Breen was 12 years old. To this day, at age 46, he can see the vet’s face when remembering. “He said, ‘There’s nothing more we can do.’” Another family dog, a Border Collie-Rough Collie cross, Peggy, also died of cancer, though she was older.

“In college, I thought, ‘There’s got to be more to this.’”

In 1995 Breen started to explore that possibility as he worked to help develop a canine genome map, the precursor to the 2004 project which he and many others conducted to generate a complete genome sequence map of the dog. During those years in England, though, as he worked on the map, he says, “I never thought for a minute we’d get the money to sequence the canine genome.”

‘Sequencing’ Changes the Game

That sequencing, however, changed the world for those studying illness in dogs – and, as it turns out, in people too.

“The availability of a high-quality full-genome sequence for the dog, largely due to the efforts of Dr. [Kerstin] Lindblad-Toh’s team at the Broad Institute in Boston, revolutionized the way we are able to approach canine genetics,” he says. “Imagine the genome sequence being printed on the pages of a book. My own lab played a key role in stamping page numbers on each page, then helping develop a contents page. Now that we know how the dog genome is organized in healthy dogs, we are able to look at how the genome is reorganized in dog cancer cells.”

In terms of cancer, one of the biggest breakthroughs since the sequencing project was “proving conclusively that chromosomal changes in a variety of cancers are shared between humans and dogs,” he says. “Effectively, we and dogs are just different organizations of the same collection of ancestrally related genes.” For example, in human meningioma – an intracranial malignancy – a characteristic chromosome change involves over 500 genes on human chromosome 22. Dogs get the same tumors and also have several hundred genes involved. “However, only about 10 of these genes are shared with humans. So what we showed is that if we consider dogs and people as one, then look at what overlaps, it’s those shared genes that highlight the major drivers in the cancer process. At a practical level, this approach allows us to reduce the number of genes we need to look at to find new treatments, going from several hundred to just a handful.”

Another reason studying the canine disease makes sense is that cancers that are rare in humans may be much more common in dogs, Breen says. He cites bone cancer as an example. “Fewer than 1,000 people are diagnosed with bone cancer each year, while maybe 50,000 dogs are. We ignore whether it’s in dogs or people, focus on the cancer, and get to the biology faster.”

Breen says the model is working. “It’s working pretty well. In the next three to five years, there will be some tremendous advances in what we know about the genetic basis for cancer. Most of that will come from dogs, then used to help people.”

From Diagnosis to Prognostication

While traditional pathology – looking at tissues under a microscope – is good for diagnosing disease, when Breen and others started looking at the chromosomes within a cell, they could see that they were “reorganizing in particular patterns,” he says. “That kind of tells us that it’s not just random. If the genetic makeup of those cancers is highly similar between patients, one has to question whether it is random.

“When we always find a particular chromosome alteration associated with a specific cancer in dogs, it’s now classified as diagnostic,” he says.

“Now, when we have a whole barrage of information about which of those patients responded to which kind of chemotherapy, the field moves from diagnosis to prognostication.” The aberration of that particular chromosome allows Breen to identify which therapies will offer “maximum survival chances.”

While it’s unlikely that pharmaceutical companies will develop drugs specifically for canine cancers, they will plough money into new therapies if they can benefit people.

The types of chromosomal changes seen in dog cancers are exactly the same as those seen in human cancers. And, as it turns out, the same drugs that cure some human cancers will cure the same canine cancers.

“It’s given us a new opportunity to go into the cancers that our dogs get, and instead of just saying to the mums and dads of the dogs, ‘Your dog’s got cancer, and there’s very little we can do,’ we can say, ‘Your dog has this particular kind of cancer with this particular abnormality,’ and we can prolong the life of their dogs with a paramount quality of life.”

However, treatment does not yet exist for every type of cancer that will benefit every dog diagnosed with it.

“Personally, I would not treat my dogs’ cancer if the only treatment is one that would make them feel really, really sick,” he says. The question is: Will this treatment have a significant effect on its quality of life? Will it give six to 12 months of life with a wagging tail, not six to 12 months with a poor quality of life?

“Genomics is providing us with the opportunities to think of new options,” Breen says. “It is interesting to consider that some of the major discoveries in cancer research over the next few years may actually come from studies of cancer in our pet dogs. Dogs have been our loyal companions for thousands of years, and are still here today to help us unlock some of nature’s most intriguing puzzles about cancers. We owe them a great deal.”

Susan Chaney has been on the editorial side of publishing since 1990, starting her career as a newspaper features writer and editor. A lifelong lover of dogs, Susan has lived with German Shepherds, Labs, Yorkies, an Irish Setter, a Great Dane-Bloodhound mix, a Sheltie and currently a Chihuahua mix of unknown pedigree. She was the editor of Dog Fancy magazine, content editor of DogChannel.com and group editor of Dog World, Dogs USA, Puppies USA, Natural Dog, Cat Fancy, Cats USA and Kittens USA from March 2005 to December 2009 when she left her position to work at home, part-time. Susan lives in Long Beach, Calif., with her artist husband, Tim, that Chi mix and two big cats. As an editor and writer for Best In Show Daily, she is reveling in the amalgam of three loves: writing, editing and dogs.

Fascinating. It is easy to tell how brilliant Dr Breen is, but his ability to explain it so someone like me can understand it tells me he is far more brilliant than I can understand. Thank you Dr Breen for your work. I am delighted it is associated with my alma mater, North Carolina State University!